1. Field of the Invention
The present invention relates to novel sulfated and phosphated saccharide derivatives, process for the preparation of the same and use thereof as well as an anti-inflammatory agent containing the derivative as an effective ingredient thereof.
2. Related Arts
In recent years, many adhesion molecules have been identified which concern direct cell contact between cells per se or cell and exo-cellular matrix. These adhesion molecules are classified into groups of selectin family, immunoglobulin family, integrin family, CD44 and the like in view of those structural characteristics, and elucidation of various functions thereof have energetically been made. Many of cell adhesion molecules belonging to the selectin family concern immunophlogistic reactions.
At the present time, 3 type cell adhesion molecules (L-selectin, E-selectin and P-selectin) have been known as those belonging to the selectin family. Among them, L-selectin is expressed on a lymphocyte, neutrocyte and monocyte, and it has been considered as concerning to homing of the lymphocyte and adhesion of inflamed region to vascular endothelium cells. E-selectin is a protein to be expressed on inflammatory vascular endothelium cells by stimulation of inflammatory cytokine, and mediates the cell adhesion of a neutrocyte, monocyte and the like. While, P-selectin expresses on activated vascular endothelium cells and activated platelets, and mediates cell adhesion between a platelet and leukocyte or the vascular endothelium cell and leukocyte. It become clear that these selectins concern rolling on the surface of vascular endothelium cells of the leukocyte rather than those powerful cell adhesing action thereto, which rolling occurs prior to the cell adhesion "J. IMMUNOL.", Vol. 153,page 3917 (1994)!.
Recently, saccharide ligands recognizing these selectins have been elucidated in molecular level "NATURE", Vol. 367, page 532 (1994); and "BIOCHEMISTRY", Vol. 33, page 1332 (1994)!. Particularly, it has been found that Sialyl Lewis X and Sialyl Lewis A is a common ligand of E-, L- and P-selectins "SCIENCE", Vol. 250, page 1130 (1990); "SCIENCE", Vol. 250, page 1132 (1990); "PROC. NATL. ACAD. SCI. USA", Vol. 88, page 6224 (1991); "BIOCHEM, BIOPHY. RES. COM.", Vol. 179, page 713 (1991) and "J. BIOL. CHEM.", Vol. 269, page 19663 (1994)!, and various derivatives thereof have been synthesized "PROC. NATL. ACAD. SCI. USA", Vol. 88, page 10372 (1991); "CARBOHYDR. RES.", Vol. 229, page cl (1992); "CARBOHYDR. RES.", Vol. 257, page 67 (1994) and "BIOSCI. BIOTECH. BIOCHEM." Vol. 59, page 1091 (1995)!. Further, it has been found that a sulfated saccharide chain as in that of sulfatides and a phosphated poly alcohols strongly bind to selectins and more particularly to P- and L-selectins and thus such a report has been issued that such compounds may show anti-inflammatory action "CELL", Vol. 67, page 35 (1991); "BIOCHEM. BIOPHY. RES. COM.", Vol. 181, page 1223 (1991); "BIOCHEM. BIOPHY. RES. COM.", Vol. 190, page 426 (1993) and "INT. IMMUNOL.", Vol. 7, page 1107 (1995)!.
On the other hand, an acute lung damage model using cobra venom factor (CVF) has been established as selectin depending inflammation model "J. CLIN. INVEST.", Vol. 88, page 1396 (1991); "J. CLIN. INVEST.", Vol. 90, page 1600 (1992) and "J. IMMUNOL.", Vol. 151, page 6410 (1993)!.
Recently, such reports have been issued as on screening using anti-selectin antibody "J. IMMUNOL." Vol. 152, page 832 (1994)!, Sialyl Lewis X "NATURE", Vol. 364, page 149 (1993) and "J. EXP. MED.", Vol. 178, page 623 (1993)!or sulfatide "INT. IMMUNOL.", Vol. 7, page 1107 (1995)! and the like, and thus it has been recognized that inhibition of cell adhesion due to selectin shows an inflammatory effect in various inflammatory reactions such as ischemia reperfusion disease, asthma, skin inflammation, lung injury due to activated complements, a shock caused by bleeding or external wound and rheumatism.
As sulfatide analogues, P. A. Ward et al. have reported that sulfatide and synthetic sulfated galactose derivatives (containing 2-tetradesyl haxadesyl .beta.-D-galactopyranoside 3-sulfate) shows inflammation inhibition effect, in case of using 2 type lung injury models, namely an inflammatory model caused activation of whole body complements by administration of CVF and another inflammatory model administrated lgG immunocomplex "INT. IMMUNOL.", Vol. 7, page 1107 (1995)!. Further, Y. Suzuki et al. have confirmed through in vitro test using a plastic plate that natural and chemically synthesized sulfated glycolipids containing 2-tetradesyl hexadesyl .beta.-D-galactopyranoside 3-sulfate and 2-tetradesyl hexadesyl O-.beta.-D-galactopyranosyl-(1.fwdarw.4)-.beta.-D-glucopyranoside 3'-sulfate! show a binding specificity to L-selectin "BIOCHEM. BIOPHY. RES. COM.", Vol. 190, page 426 (1993)!. These results give a suggestions that the selectin adhesion inhibitor may be employed as an effective ingredient of a novel curing or preventive drug for its clinical use.